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Micro-Formulating for Dermal Drug Delivery

Industry is beginning to appreciate how formulation microstructure makes a fundamental contribution to dermal drug delivery – and this new understanding emphasizes the key role of excipients.

03/17/2016

Norman Richardson’s career has taken him from cancer research to BASF’s Skin Delivery group. His experience as a customer, he argues, makes him a better vendor. Richardson’s clients include Lakshmi Raghavan (CEO of Solaris Pharma Corporation) and Padam Bansal (Senior VP R&D of Amneal Pharmaceuticals) – both based in New Jersey, USA. Bansal focuses on Amneal’s topical drug delivery pipeline, while Raghavan, who started out in physics, is now hooked by dermal drug delivery.

All three are fascinated by the challenges of dermal drug delivery, but the skin is a complex organ, and its structure and role present specific problems for formulation teams. Perhaps a better understanding of the complex 3D structures found in semi-solid formulations will help drug developers cross this barrier.

Barriers to entry

Raghavan reminds us of the amazing role of our skin; “It’s a thin, 15 micron layer that regulates the temperature of your body, stops you drying out, and keeps out foreign bodies – it’s extraordinary.” However, such properties also present a fundamental problem for pharma: the skin keeps out drugs – very effectively. A great variety of formulations have been developed to overcome this obstacle, such as ointments, gels, creams, lotions, spray on products, films, and patches, for example, but they all must address the same four challenges:

effective transfer of product from its container to the appropriate skin surface in a way that is acceptable in terms of appearance, odor and touch.

pervasion of API through the dense, protein- and lipid-rich skin layer known as the stratum corneum.

avoidance of product-induced irritation or inflammation.

delivery of API to the correct anatomical compartment, whether local or systemic.

According to Richardson, understanding how excipients can address these challenges can determine success in dermal drug delivery. Raghavan expands, “Hydrophilic molecules can’t easily penetrate the stratum corneum – but hydrophobic molecules are blocked by the underlying dermis. So your product needs to have a balance of hydrophilic and lipophilic properties, which excipients can help achieve,” he says.

“To get systemic uptake,” adds Bansal, “you may need penetration enhancers to help carry the drug through the skin. If you don’t use a penetration enhancer, then you may be forced to apply the drug over a greater surface area. But at the same time you need to avoid unwanted binding of API to other excipients, as this could inhibit absorption.”

With all these hurdles, it is perhaps not surprising that after decades of research, only ~25 transdermally-delivered drugs are on the market. But this could change. Richardson says, “Formulation design, not least attention to formulation microstructure, will help overcome these delivery challenges.”

Micro construction

But what exactly is formulation microstructure? “The ingredients of a topical formulation, such as polymer, medium, and API, interact in various ways to form a structural relationship,” says Raghavan. “Ideally, this structure should hold the drug in a stable and homogeneous state. Microstructure features include aspects such as the droplet sizes in an emulsion, the size distribution of the API particles, and the homogeneity of API dispersion in the formulation.”

Interest in microstructure is as much pragmatic as academic – Bansal points out that microstructure affects product properties such as rheology, viscosity and spreadability, and therefore influences product efficacy. Raghavan concurs, adding that the rate of drug release is also affected by microstructure. Richardson provides evidence for the practical importance of understanding microstructure from his experience with a topical anti-inflammatory that had developed batch-to-batch stability issues. “The first thing I did was to look under the microscope. I immediately saw that the API crystals in the unstable formulation were significantly smaller, suggesting the API dissolution rate was higher and oxidation/degradation more rapid. The solution was to increase crystal size. You wouldn’t have worked that out without paying attention to microstructure.”

But how easy is it to modulate formulation microstructure? Richardson is clear; the choice of excipients is key – but to make an informed choice, you must do your homework; namely detailed studies (using tools like microscopy and differential scanning calorimetry) to show how excipient selection can influence the microstructure of semi-solid formulations, and to provide a firm understanding of how the resulting microstructure affects formulation performance. “We’ve used microstructure studies to identify critical aspects of PEG mixtures, such as the ratio of solid to liquid PEG that gives best stability,” Richardson says. “With that knowledge, we can make intelligent decisions about the optimal mixture of high and low molecular weight PEGs, and the best process parameters.”

“We found that the viscosity and spreadability of a PEG-based ointment were fine in low volume batches but unsatisfactory after scale-up,” Bansal adds. “The viscosity changes were caused by altered mixing and heating parameters at larger scale, and microstructure studies showed that by keeping the heating step below a certain temperature, the desired product attributes were preserved.”

Raghavan agrees. “The exact form of the microstructure can be affected by the formulation process – the temperature at which you mix the ingredients and the cooling rate, for example. If you cool it too fast, the viscosity drops from say 100,000 to 30-40,000; but by cooling it slowly you can preserve the microstructure.”

Microstructure is certainly a hot topic – there was standing-room only at Richardson’s recent seminar at the American Association of Pharmaceutical Sciences event held in Orland, Florida, last year. The interest reflects a broad acceptance that the performance and functionality of semi-solid formulations is driven not only by the individual ingredients in the formulation, but also by the complex structures that form when these ingredients are mixed together. “The excipients assemble into physical structures, and these structures drive product functionality – they are as important as the API,” says Richardson.

And that is why Bansal – and others like him – turn to experts for advice. “In topical drug products, excipients are critical for API delivery. That’s why we work closely with our suppliers and manufacturers, so we know what’s going to happen if we subject an excipient to higher temperatures or longer mixing times,” he says.

The new appreciation of microstructure is also influencing regulatory oversight. “Regulators increasingly request information about the localization or state of the API in the microstructure, such as its crystalline form, aggregation, and homogeneity,” Richardson says. “Addressing these questions requires microscopy and rheology, both of which are routinely employed by my colleagues and I.”

“Put simply,” concludes Raghavan, “it’s clear that microstructure studies are an essential development tool that can help prevent successive failed formulations.”

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